1-[alkyl],1-[(heteroaryl)alkyl] and 1-[aryl]alkyl]-7pyridinyl-imidazo[1,2-alpha]pyrimidin-5(1h)-one derivatives

ABSTRACT

The invention relates to an imidazo[1,2-a]pyrimidone derivative represented by formula (1) or a salt thereof, wherein: X represents a bond, an ethenylene group, and ethenylene group, a methylene group optionally substituted by one or two groups selected from a C 1-6  alkyl group, a hydroxy group and a C 1-4  alkoxy group; a carbonyl group, an oxygen atom, a sulfur atom, a sulfonyl group, a sulfoxide group or a nitrogen atom being optionally substituted by a C 1-6  alkyl group; R1 represents a 2,3 or 4-pyridyl group optionally substituted by a C 1-4  alkyl group, C 1-4  alkoxy group or a halogen atom; R2 represents a C 1-4  alkyl group, perhalogenated alkyl group, a C 1-3  halogenated alkyl group, a benzyl group, a phenyl ring, a naphthyl ring, 5,6,7,8-tetrahydronaphthyl ring, a pyridyl ring, an indole ring, a pyrrole ring, a thiophene ring, a furan ring or an imidazole ring, the benzyl group and the rings being optionally substituted by 1 to 4 substituents selected from a C 1-4  alkyl group, a phenyl ring, a halogen atom, a C 1-2  perhalogenated alkyl group, a C 1-3  halogenated alkyl group, a hydroxyl group, a C 1-4  alkoxy group, a nitro, a cyano, an amino, a C 1-6  monoalkylamino group or a C 2-10  dialkylamino group; and n represents 0 to 3. The invention relates also to a medicament comprising the said derivative or a salt thereof as an active ingredient which is used for preventive and/or therapeutic treatment of a neurodegenerative disease caused by abnormal activity of GSK3β, such as Alzheimer disease.

TECHNICAL FIELD

[0001] The present invention relates to compounds that are useful as anactive ingredient of a medicament for preventive and/or therapeutictreatment of neurodegenerative diseases caused by abnormal activity ofGSK3β.

BACKGROUND ART

[0002] GSK3β (glycogen synthase kinase 3β) is a proline directed serine,threonine kinase that plays an important role in the control ofmetabolism, differentiation and survival. It was initially identified asan enzyme able to phosphorylate and hence inhibit glycogen synthase. Itwas later recognized that GSK3β was identical to tau protein kinase 1(TPK1), an enzyme that phosphorylates tau protein in epitopes that arealso found to be hyperphosphorylated in Alzheimer's disease and inseveral tauopathies. Interestingly, protein kinase B (AKT)phosphorylation of GSK3β results in a loss of its kinase activity, andit has been hypothesized that this inhibition may mediate some of theeffects of neurotrophic factors. Moreover, phosphorylation by GSK3β ofβ-catenin, a protein involved in cell survival, results in itsdegradation by an ubiquitinilation dependent proteasome pathway.

[0003] Thus, it appears that inhibition of GSK3β activity may result inneurotrophic activity. Indeed there is evidence that lithium, anuncompetitive inhibitor of GSK3β, enhances neuritogenesis in some modelsand also increases neuronal survival, through the induction of survivalfactors such as Bcl-2 and the inhibition of the expression ofproapoptotic factors such as P53 and Bax.

[0004] Recent studies have demonstrated that β-amyloid increases theGSK3β activity and tau protein phosphorylation. Moreover, thishyperphosphorylation as well as the neurotoxic effects of β-amyloid areblocked by lithium chloride and by a GSK3β antisense mRNA. Theseobservations strongly suggest that GSK3β may be the link between the twomajor pathological processes in Alzheimer's disease: abnormal APP(Amyloid Precursor Protein) processing and tau proteinhyperphosphorylation.

[0005] Although tau hyperphosphorylation results in a destabilization ofthe neuronal cytoskeleton, the pathological consequences of abnormalGSK3β activity are, most likely, not only due to a pathologicalphosphorylation of tau protein because, as mentioned above, an excessiveactivity of this kinase may affect survival through the modulation ofthe expression of apoptotic and antiapoptotic factors. Moreover, it hasbeen shown that β-amyloid-induced increase in GSK3β activity results inthe phosphorylabon and, hence the inhibition of pyruvate dehydrogenase,a pivotal enzyme in energy production and acetylcholine synthesis.

[0006] Altogether these experimental observations indicate that GSK3βmay find application in the treatment of the neuropathologicalconsequences and the cognitive and attention deficits associated withAlzheimer's disease, as well as other acute and chronicneurodegenerative diseases. These include, in a non-limiting manner,Parkinson's disease, tauopathies (e.g. frontotemporoparietal dementia,corticobasal degeneration, Pick's disease, progressive supranuclearpalsy) and other dementia including vascular dementia; acute stroke andothers traumatic injuries; cerebrovascular accidents (e.g. age relatedmacular degeneration); brain and spinal cord trauma; peripheralneuropathies; retinopathies and glaucoma.

[0007] In addition GSK3β may find application in the treatment of otherdiseases such as: Non-insulin dependent diabetes (such as diabetes typeII) and obesity; manic depressive illness; schizophrenia; alopecia;cancers such as breast cancer, non-small cell lung carcinoma, thyroidcancer, T or B-cell leukemia and several virus-induced tumors.

DISCLOSURE OF THE INVENTION

[0008] An object of the present invention is to provide compounds usefulas an active ingredient of a medicament for preventive and/ortherapeutic treatment of a disease caused by abnormal GSK3β activity,more particularly of neurodegenerative diseases. More specifically, theobject is to provide novel compounds useful as an active ingredient of amedicament that enables prevention and/or treatment of neurodegenerativediseases such as Alzheimer's disease. Thus, the inventors of the presentinvention have identified compounds possessing inhibitory activityagainst GSK3β. As a result, they found that compounds represented by thefollowing formula (I) had the desired activity and were useful as anactive ingredient of a medicament for preventive and/or therapeutictreatment of the aforementioned diseases.

[0009] The present invention thus provides imidazo[1,2-a]pyrimidonederivatives represented by formula (I) or salts thereof, solvatesthereof or hydrates thereof:

[0010] wherein:

[0011] X represents a bond, an ethenylene group, an ethynylene group, amethylene group optionally substituted by one or two groups selectedfrom a C₁₋₆ alkyl group, a hydroxy group and a C₁₋₄ alkoxy group;

[0012] a carbonyl group, an oxygen atom, a sulfur atom, a sulfonylgroup, a sulfoxide group or a nitrogen atom being optionally substitutedby a C₁₋₆ alkyl group;

[0013] R1 represents a 2, 3 or 4-pyridyl group optionally substituted bya C₁₋₄ alkyl group, C₁₋₄ alkoxy group or a halogen atom;

[0014] R2 represents a C₁₋₆ alkyl group, a C₁₋₂ perhalogenated alkylgroup, a C₁₋₃ halogenated alkyl group, a benzyl group, a phenyl ring, anaphthyl ring, 5,6,7,8-tetrahydronaphthyl ring, a pyridyl ring, anindole ring, a pyrrole ring, a thiophene ring, a furan ring or animidazole ring, the benzyl group and the rings being optionallysubstituted by 1 to 4 substituents selected from a C₁₋₆ alkyl group, aphenyl ring, a halogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃halogenated alkyl group, a hydroxyl group, a C₁₋₄ alkoxy group, a nitro,a cyano, an amino, a C₁₋₆ monoalkylamino group or a C₂₋₁₀ dialkylaminogroup;

[0015] and n represents 0 to 3.

[0016] According to another aspect of the present invention, there isprovided a medicament comprising as an active ingredient a substanceselected from the group consisting of the pyrimidone derivativesrepresented by formula (I) and the physiologically acceptable saltsthereof, and the solvates thereof and the hydrates thereof. As preferredembodiments of the medicament, there are provided the aforementionedmedicament which is used for preventive and/or therapeutic treatment ofdiseases caused by abnormal GSK3β activity, and the aforementionedmedicament which is used for preventive and/or therapeutic treatment ofneurodegenerative diseases and in addition other diseases such as:Non-insulin dependent diabetes (such as diabetes type II) and obesity;manic depressive illness; schizophrenia; alopecia; cancers such asbreast cancer, non-small cell lung carcinoma, thyroid cancer, T orB-cell leukemia and several virus-induced tumors.

[0017] As further preferred embodiments of the present invention, thereare provided the aforementioned medicament wherein the diseases areneurodegenerative diseases and are selected from the group consisting ofAlzheimer's disease, Parkinson's disease, tauopathies (e.g.frontotemporoparietal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy) and other dementia includingvascular dementia; acute stroke and others traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma, and the aforementioned medicament in the form ofpharmaceutical composition containing the above substance as an activeingredient together with one or more pharmaceutical additives.

[0018] The present invention further provides an inhibitor of GSK3βactivity comprising as an active ingredient a substance selected fromthe group consisting of the imidazo[1,2-a]pyrimidone derivatives offormula (I) and the salts thereof, and the solvates thereof and thehydrates thereof.

[0019] According to further aspects of the present invention, there isprovided a method for preventive and/or therapeutic treatment ofneurodegenerative diseases caused by abnormal GSK3β activity, whichcomprises the step of administering to a patient a preventively and/ortherapeutically effective amount of a substance selected from the groupconsisting of the imidazo[1,2-a]pyrimidone derivatives of formula (I)and the physiologically acceptable salts thereof, and the solvatesthereof and the hydrates thereof; and a use of a substance selected fromthe group consisting of the imidazo[1,2-a]pyrimidone derivatives offormula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof for the manufacture of theaforementioned medicament.

[0020] As used herein, the C₁₋₆ alkyl group represents a straight orbranched alkyl group having 1 to 6 carbon atoms, for example, methylgroup, ethyl group, n-propyl group, isopropyl group, n-butyl group,isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group,isopentyl group, neopentyl group, 1,1-dimethylpropyl group, n-hexylgroup, isohexyl group, and the like;

[0021] The C₁₋₄ alkoxy group represents an alkyloxy group having 1 to 4carbon atoms for example, methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group,tert-butoxy group, and the like;

[0022] The halogen atom represents a fluorine, chlorine, bromine oriodine atom;

[0023] The C₁₋₂ perhalogenated alkyl group represents an alkyl groupwherein all the hydrogen have been substituted by a halogen atom, forexample a CF₃ or C₂F₅;

[0024] The C₁₋₃ halogenated alkyl group represents an alkyl groupwherein at least one hydrogen has not been substituted by a halogenatom;

[0025] The C₁₋₅ monoalkylamino group represents an amino groupsubstituted by one C₁₋₅ alkyl group, for example, methylamino group,ethylamino group, propylamino group, isopropylamino group, butylaminogroup, isobutylamino group, tert-butylamino group, pentylamino group andisopentylamino group;

[0026] The C₂₋₁₀ dialkylamino group represents an amino groupsubstituted by two C₁₋₅ alkyl groups, for example, dimethylamino group,ethylmethylamino group, diethylamino group, methylpropylamino group anddiisopropylamino group;

[0027] The ethenylene and ethynylene group represents respectively thefollowing groups:

[0028] The leaving group represents a group which could be easilycleaved and substituted, such a group may be for example a tosyl, amesyl, a bromide and the like.

[0029] The compounds represented by the aforementioned formula (I) mayform a salt. Examples of the salt include, when an acidic group exists,salts of alkali metals and alkaline earth metals such as lithium,sodium, potassium, magnesium, and calcium; salts of ammonia and aminessuch as methylamine, dimethylamine, trimethylamine, dicyclohexylamine,tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine,2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, andL-glucamine; or salts with basic amino acids such as lysine,δ-hydroxylysine, and arginine. The base-addition salts of acidiccompounds are prepared by standard procedures well known in the art.

[0030] When a basic group exists, examples include salts with mineralacids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid; salts with organic acids such as methanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid,propionic acid, tartaric acid, fumaric acid, maleic acid, malic acid,oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid,cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbicacid, nicotinic acid, and salicylic acid; or salts with acidic aminoacids such as aspartic acid, and glutamic acid. The acid-addition saltsof the basic compounds are prepared by standard procedures well know inthe art which include, but are not limited thereto, dissolving the freebase in an aqueous alcohol solution containing the appropriate acid andisolating the salt by evaporating the solution, or by reacting the freebase and an acid in an organic solvent, in which case the salt separatesdirectly, or is precipitated with a second organic solvent, or can beobtained by concentration of the solution. The acids which can be usedto prepare the acid-addition salts include preferably those whichproduce, when combined with the free base, pharmaceutically-acceptablesalts, that is, salts whose anions are relatively innocuous to theanimal organism in pharmaceutical doses of the salts, so that thebeneficial properties inherent in the free base are not compromised byside effects ascribable to the anions. Although medicinally acceptablesalts of the basic compounds are preferred, all acid-addition salts arewithin the scope of the present invention.

[0031] In addition to the imidazo[1,2-a]pyrimidone derivativesrepresented by the aforementioned formula (I) and salts thereof, theirsolvates and hydrates also fall within the scope of the presentinvention. The imidazo[1,2-a]pyrimidone derivatives represented by theaforementioned formula (I) may have one or more asymmetric carbon atoms.As for the stereochemistry of such asymmetric carbon atoms, they mayindependently be in either (R) and (S) configuration, and theimidazo[1,2-a]pyrimidone derivative may exist as stereoisomers such asoptical isomers, or diastereoisomers. Any stereolsomers in pure form,any mixtures of stereoisomers, racemates and the like fall within thescope of the present invention.

[0032] Examples of preferred compounds of the present invention areshown in table 1 hereinafter. However, the scope of the presentinvention is not limited by these compounds.

[0033] Preferred compounds of the present invention represented byformula (I) include also:

[0034] (1) Compounds wherein R1 represents a 3- or 4-pyridyl group andmore preferably 4-pyridyl group, which may be substituted by a C₁₋₂alkyl group, a C₁₋₂ alkoxy group or a halogen atom; and/or

[0035] (2) X represents a bond, an ethenylene group, a methylene groupoptionally substituted, a carbonyl group, a sulfur atom, an oxygen atomor a nitrogen atom optionally substituted.

[0036] More preferred compounds of the present invention represented byformula (I) include also:

[0037] (1) Compounds wherein R1 represents an unsubstituted 4-pyridylgroup;

[0038] (2) Compounds wherein R2 represents a trifluoromethyl group, a2,2,2-trifluoroethyl, a phenyl ring, a naphthyl ring, a5,6,7,8-tetrahydronaphthyl ring or an indole ring, the rings beingoptionally substituted; and/or

[0039] (3) Compounds wherein X represents an ethenylene group, amethylene group optionally substituted, a carbonyl group, a sulfur atomor an oxygen atom.

[0040] Particularly preferred compounds of the present inventionrepresented by formula (I) include:

[0041] 1:1-[2-(phenyl)ethyl]-7-pyridin4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0042] 2: 1-[2-(1H-indol-3-yl)ethyl]-7-pyridin4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0043] 3:1-[3-(phenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0044] 4:1-[3-(1H-indol-3-yl)propyl]-7-pyridin-4ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0045] 5:1-[3-(4-methoxyphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one

[0046] 6:1-[2-(phenoxy)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one

[0047] 7:1-[3-(2-methoxyphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one

[0048] 8:1-[3-(2-chlorophenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one

[0049] 9:1-[3-(2-methylphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one

[0050]10:1-[2-(phenylthio)ethyl]-7-pyridin-4-ylimidazo[1,2a]pyrimidin-5(1H)-one,

[0051]11:1-[3-(2,5-dimethoxyphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one

[0052]12:1-[3-(4-methylphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one

[0053]13:1-[3-(4-trifluoromethylphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0054]14:1-[4-(phenyl)butyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0055]15:1-[3-(phenyl)propyl]-7-pyridin-3-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0056]16:1-(2-phenyl-2-oxo-ethyl]7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(H)-one,

[0057]17:(S)-1-(4,4,4-trifluoro-3-hydroxybutyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0058]18:1-(4,4,4-trifluorobut-2-enyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0059]19:(R)1-(4,4,4-trifluoro-3-hydroxybutyl)7-pyridinylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0060]20:1-(4,4,4-trifluorobut-1-enyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0061]21:1-[2-(2,5-dimethoxyphenyl)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one

[0062]22:1-[3-(2-fluorophenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one

[0063]23:1-(3-phenyl-3-oxo-propyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0064]24:1-[3-(pyridin-3-yl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0065]25:(S)-1-(4,4,4-trifluoro-butyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0066]26:1-[2-(2-methoxyphenyl)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0067]27:1-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0068]28:1-[2-(4-phenyl-phenyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0069]29:1-[2-(3-methoxyphenyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0070]30:1-[2-(2-naphthyl)2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0071]31:1-[2-(4-methylphenyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0072]32:1-[2-(4-fluorophenyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0073]33:1-[2-(4-chlorophenyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0074]34:1-(2-(4-fluorophenyl)-2-hydroxyethyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,

[0075]35:1-(2-naphthyl-2-hydroxyethyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,and

[0076]36:1-(2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-2-hydroxyethyl)7-pyridin-4-ylimidazo[1,2a]pyrimidin-5(1H)-one.

[0077] As a further object, the present invention concerns also methodsfor preparing the imidazo[1,2-a]pyrimidone compounds represented by theaforementioned formula (I).

[0078] These compounds can be prepared, for example, according tomethods explained below.

[0079] Preparation Method

[0080] Imidazo[1,2-a]pyrimidone compounds represented by theaforementioned formula (I) may be prepared according to scheme 1.

[0081] (In the above scheme the definition of R1, R2, X and n are thesame as those already described for compound of formula (I)).

[0082] The 7-pyridin-4-ylimidazo[1,2a]pyrimidin-5(1H)-one derivativerepresented by the above formula (III), wherein R1 is as defined forcompound of formula (I), is allowed to react with a base such as sodiumhydride, sodium carbonate or potassium carbonate in a solvent such asN,N-dimethylformamide, N-methylpyrrolidine, N,N-dimethylacetamide orchloroform at a suitable temperature ranging from 0 to 130° C. underordinary air, then with a compound of formula (II), wherein R2, X and nare as defined for compound of formula (I) and L represents a leavinggroup preferably bromide or mesyl group, is added to obtain the compoundof the aforementioned formula (I).

[0083] Compound of formula (II) are commercially available or may besynthesized according to well-known methods of one skilled in the art.The compound of formula (III) may be prepared according to the methoddefined in scheme 2.

[0084] (In the above scheme the definition of R1 is the same as alreadydescribed.)

[0085] According to this method, the 3-ketoester of formula (V) isallowed to react with a 2-aminoimidazole of formula (IV). The reactionmay be carried out in the presence of an ammonium salt such as ammoniumacetate, in a alcoholic solvent such as methanol, ethanol and the likeor without, at a suitable temperature ranging from 25°-140° C. underordinary air.

[0086] Compounds of formula (V) or (IV) are commercially available ormay be synthesized according to well-known methods of one skilled in theart.

[0087] For example compounds of formula (V), wherein R1 represent apyridyl group optionally substituted by a C₁₋₄ alkyl group, C₁₋₄ alkoxygroup or a halogen atom, can be prepared by reacting a nicotinic acidoptionally substituted by a C₁₋₄ alkyl group, C₁₋₄ alkoxy group or anhalogen, with a malonic acid monoester. The reaction can be carried outusing methods well known to one skilled in the art, such as for examplein presence of a coupling agent such as 1,1′-carbonylbis-1H-imidazole ina solvent such as tetrahydrofuran at a temperature ranging from 20 to70° C.

[0088] In the above reactions, protection or deprotection of afunctional group may sometimes be necessary. A suitable protecting groupPg can be chosen depending on the type of the functional group, and amethod described in the literature may be applied. Examples ofprotecting groups, of protection and deprotection methods are given forexample in Protective groups in Organic Synthesis Greene et al., 2nd Ed.(John Wiley & Sons, Inc., New York).

[0089] The compounds of the present invention have inhibitory activityagainst GSK3β. Accordingly, the compounds of the present invention areuseful as an active ingredient for the preparation of a medicament,which enables preventive and/or therapeutic treatment of a diseasecaused by abnormal GSK3β activity and more particularly ofneurodegenerative diseases such as Alzheimer's disease. In addition, thecompounds of the present invention are also useful as an activeingredient for the preparation of a medicament for preventive and/ortherapeutic treatment of neurodegenerative diseases such as Parkinson'sdisease, tauopathies (e.g. frontotemporoparietal dementia, corticobasaldegeneration, Pick's disease, progressive supranuclear palsy) and otherdementia including vascular dementia; acute stroke and others traumaticinjuries; cerebrovascular accidents (e.g. age related maculardegeneration); brain and spinal cord trauma; peripheral neuropathies;retinopathies and glaucoma; and other diseases such as non-insulindependent diabetes (such as diabetes type II) and obesity; manicdepressive illness; schizophrenia; alopecia; cancers such as breastcancer, non-small cell lung carcinoma, thyroid cancer, T or B-cellleukemia and several virus-induced tumors.

[0090] The present invention further relates to a method for treatingneurodegenerative diseases caused by abnormal activity of GSK3β and ofthe aforementioned diseases which comprises administering to a mammalianorganism in need thereof an effective amount of a compound of theformula (I).

[0091] As the active ingredient of the medicament of the presentinvention, a substance may be used which is selected from the groupconsisting of the compound represented by the aforementioned formula (I)and pharmacologically acceptable salts thereof, and solvates thereof andhydrates thereof. The substance, per se, may be administered as themedicament of the present invention, however, it is desirable toadminister the medicament in a form of a pharmaceutical compositionwhich comprises the aforementioned substance as an active ingredient andone or more pharmaceutical additives. As the active ingredient of themedicament of the present invention, two or more of the aforementionedsubstances may be used in combination. The above pharmaceuticalcomposition may be supplemented with an active ingredient of anothermedicament for the treatment of the above mentioned diseases. The typeof pharmaceutical composition is not particularly limited, and thecomposition may be provided as any formulation for oral or parenteraladministration. For example, the pharmaceutical composition may beformulated, for example, in the form of pharmaceutical compositions fororal administration such as granules, fine granules, powders, hardcapsules, soft capsules, syrups, emulsions, suspensions, solutions andthe like, or in the form of pharmaceutical compositions for parenteraladministrations such as injections for intravenous, intramuscular, orsubcutaneous administration, drip infusions, transdermal preparations,transmucosal preparations, nasal drops, inhalants, suppositories and thelike. Injections or drip infusions may be prepared as powderypreparations such as in the form of lyophilized preparations, and may beused by dissolving just before use in an appropriate aqueous medium suchas physiological saline. Sustained-release preparations such as thosecoated with a polymer may be directly administered intracerebrally.

[0092] Types of pharmaceutical additives used for the manufacture of thepharmaceutical composition, content ratios of the pharmaceuticaladditives relative to the active ingredient, and methods for preparingthe pharmaceutical composition may be appropriately chosen by thoseskilled in the art. Inorganic or organic substances, or solid or liquidsubstances may be used as pharmaceutical additives. Generally, thepharmaceutical additives may be incorporated in a ratio ranging from 1%by weight to 90% by weight based on the weight of an active ingredient.

[0093] Examples of excipients used for the preparation of solidpharmaceutical compositions include, for example, lactose, sucrose,starch, talc, cellulose, dextrin, kaolin, calcium carbonate and thelike. For the preparation of liquid compositions for oraladministration, a conventional inert diluent such as water or avegetable oil may be used. The liquid composition may contain, inaddition to the inert diluent, auxiliaries such as moistening agents,suspension aids, sweeteners, aromatics, colorants, and preservatives.The liquid composition may be filled in capsules made of an absorbablematerial such as gelatin. Examples of solvents or suspension mediumsused for the preparation of compositions for parenteral administration,e.g. injections, suppositories, include water, propylene glycol,polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and thelike. Examples of base materials used for suppositories include, forexample, cacao butter, emulsified cacao butter, lauric lipid, witepsol.

[0094] The dose and frequency of administration of the medicament of thepresent invention are not particularly limited, and they may beappropriately chosen depending on conditions such as a purpose ofpreventive and/or therapeutic treatment, a type of a disease, the bodyweight or age of a patient, severity of a disease and the like.Generally, a daily dose for oral administration to an adult may be 0.01to 1,000 mg (the weight of an active ingredient), and the dose may beadministered once a day or several times a day as divided portions, oronce in several days. When the medicament is used as an injection,administrations may preferably be performed continuously orintermittently in a daily dose of 0.001 to 100 mg (the weight of anactive ingredient) to an adult.

CHEMICAL EXAMPLES

[0095] The present invention will be explained more specifically withreference to the following general examples, however, the scope of thepresent invention is not limited to these examples.

Example 1

[0096] (Compound N^(o) 1 of Table 1)

[0097]1-[2-(Phenyl)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one(Z)but-2-enedioate (1:1)

[0098] 1.1. 7-Pyridin4-ylimidazo[1,2a]pyrimidin-5(1H)-one

[0099] A mixture containing 7.31 g (38 mmol) of ethyl3-(4-pyridyl)-3-oxopropionate, 5 g (38 mmol) of 2-aminoimidazolehemisulfate and 5.86 g (76 mmol) of ammonium acetate was heated at 140°C. during 18 h. The cooled mixture was treated with 30 ml ofacetonitrile and filtered and the precipitate was added to water andheated at reflux temperature for 30 min. The resulting solution wascooled and the precipitate recovered by filtration. The crude productthus obtained was recrystallised from ethanol to give 3.0 g of pureproduct as a gray solid.

[0100] Mp: 368-370° C.

[0101] 1.2.1-[2-(Phenyl)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H) one(Z)-but-2-enedioate (1:1)

[0102] A suspension of 0.1 g (0.47 mmol) of7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one in 4 ml of anhydrousN,N-dimethylformamide was treated with 72 mg (0.52 mmol) of potassiumcarbonate and the resulting mixture was heated at 70° C. for 30 min. 96mg (0.52 mmol) of 2-(phenyl)ethyl bromide was added and the reactionmixture was heated at 130° C. during 1 h.

[0103] The cooled solution was treated with water and extracted withethyl acetate. The organic phase was dried and evaporated to give crudeproduct which was purified by silica gel chromatography, eluting withdichloromethane/methanol in the proportions 100/0 to 95/5. The 0.338 gof pure product obtained in the form of free base was dissolved in hotethanol and treated with 1 equivalent of (Z)-but-2-enedioic acid. Thecooled solution was filtered to afford 0.12 g of solid.

[0104] Mp: 190-192° C.

Example 2

[0105] (Compound N^(o) 4 of table 1)

[0106]1-[3-(1H-Indol-3-yl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one.

[0107] 2.1. 3-(1H-Indol-3-yl)propanol (J. Med. Chem. (1995), 38(11),1998)

[0108] To a suspension of 4.8 g (126.8 mmol) of lithium aluminum hydridein 240 ml of diethylether at 0° C. was added dropwise 10 g (52.8 mmol)of 3-(1H-indol-3-yl)propanoic acid dissolved in 430 ml of diethyletherand the resulting mixture stirred at room temperature for 1 h.

[0109] The reaction mixture was diluted with 100 ml of diethylether at0° C. and treated with excess of a saturated aqueous solution of sodiumsulfate. Further solid sodium sulfate was added and the organic phasewas filtered to remove salts. The solvent was evaporated to dryness togive 9 g (98%) of product as an oil.

[0110] 2.2. 3-(1H-Indol-3-yl)propyl bromide (Chem. Pharm. Bull. (1988),36(8), 2853)

[0111] To a solution of 2 g (11.41 mmol) of 3-(1H-indol-3-yl)propanol in40 ml of dioxane was added at room temperature 5.3 g (12.55 mmol) ofdibromotriphenylphosphorane and the resulting solution was stirredduring 18 h. An excess of cyclohexane was added and the resultingprecipitate was filtered and discarded. The solvent was evaporated todryness to give 2.7 g (99%) of product as an oil which was used in thesubsequent step without further purification.

[0112] 2.3.1-[3-(1H-Indol-3-yl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one.

[0113] To a suspension of 0.10 g (0.47 mmol) of7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one in 3 ml of anhydrousN,N-dimethylformamide was added 0.072 g (0.52 mmol) of potassiumcarbonate and the resulting mixture was heated at 130° C. during 10 min.There is added 0.116 g (0.52 mmol) of 3-(1H-indol-3-yl)propyl bromideand heating is continued for 16 h.

[0114] The cooled suspension is treated with water, extracted with ethylacetate and the organic extracts dried over sodium sulfate. The crudeproduct was purified by chromatography on silica gel eluting with amixture dichloromethane/methanol/ammonia in the ratio 90/10/1 to afford0.11 g of pure product.

[0115] Mp: 201-203° C.

Example 3

[0116] (Compound N^(o) 10 of table 1)

[0117]1-[2-(Phenylthio)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-onehydrochloride (1:1)

[0118] To a suspension of 0.2 g (0.94 mmol) of7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one in 4.5 ml of anhydrousN,N-dimethylformamide was added 0.169 g (1.23 mmol) of potassiumcarbonate and the resulting mixture was heated at 70° C. during 20 min.There was added 0.267 g (1.23 mmol) of 2-bromoethylphenylsulphide andheating was continued at 130° C. during 1.5 h.

[0119] Water was added to the cooled mixture and the resulting solutionextracted with ethyl acetate. The combined extracts were washed withwater and evaporated. The crude product was purified by chromatographyon silica gel eluting with a mixture of dichloromethanelmethanol in theproportions 100/0 to 96/4 to obtain pure compound as free base. Thecompound was converted to the hydrochloride salt by addition ofhydrochloric acid to an ethanolic solution of the free base. There isobtained 0.133 g of product as a white solid.

[0120] Mp: 219-221° C.

Example 4

[0121] (Compound N^(o) 6 of table 1)

[0122]1-[2-(Phenoxy)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one(Z)-but-2-enedioate (1:1)

[0123] To a suspension of 0.4 g (1.88 mmol) of7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one in 6 ml of anhydrousN,N-dimethylformamide was added 0.312 g (2.25 mmol) of potassiumcarbonate and the resulting mixture was heated at 70° C. during 30 min.There was added 0.378 g (1.88 mmol) of 2-phenoxyethyl bromide andheating was continued at 130° C. during 2 h.

[0124] Water was added to the cooled mixture and the resulting solutionextracted with ethyl acetate. The combined extracts were washed withwater and evaporated. The crude product was purified by chromatographyon silica gel eluting with a mixture of dichloromethane/methanol in theproportions 100/0 to 96/4 to obtain pure compound as free base. Theproduct obtained in the form of free base was converted to the salt bytreatment with one equivalent of (Z)-but-2-enedioic acid. There isobtained thus 0.217 g of final product.

[0125] Mp: 158-160° C.

[0126] A list of chemical structures and physical data for compounds ofthe aforementioned formula (I) illustrating the present invention isgiven in table 1. The compounds have been prepared according to themethods of the example.

[0127] In the table, R1 is an unsubstituted 4-pyridyl group (4-py) or3-pyridyl group (3-py), Ph represents a phenyl group, (S) indicates thestereochemistry of the carbon atom, and “______” in the structure of R2represents the bond attached to X. TABLE 1

N° R1 X R2 n Mp ° C. salt 1 4-py CH₂ Ph 1 190-192 (1:1)(Z)-but-2-enedioate 2 4-py CH₂

1 195-198 (1:1) (Z)-but-2-enedioate 3 4-py CH₂ Ph 2 150-152 (1:1)(Z)-but-2- enedioate 4 4-py CH₂

2 201-203 base 5 4-py CH₂

2 170-172 (1:1) (Z)-but-2-enedioate 6 4-py O Ph 2 158-160 (1:1)(Z)-but-2-enedioato 7 4-py CH₂

2 192-194 (1:1) hydrochloride 8 4-py CH₂

2 197-199 (1:1) hydrochloride 9 4-py CH₂

2 189-191 (1:1) hydrochloride 10 4-py S

2 219-221 (1:1) hydrochloride 11 4-py CH₂

2 207-209 (1:1) hydrochloride 12 4-py CH₂

2 200-202 (1:1) hydrochloride 13 4-py CH₂

2 204-206 (1:1) hydrochloride 14 4-py CH₂ Ph 3 206-208 (1:1)hydrochloride 15 3-py CH₂ Ph 2 184-185 (1:1) hydrochloride 16 4-py CO Ph1 264-268 hydrochloride 17 4-py CH(OH) CF₃ 2 220-222 Base (S) 18 4-py ═CF₃ 1 187-188 base (trans) 19 4-py CH(OH) CF₃ 2 219-220 base (R) 20 4-py═ CF₃CH₂ 0 221-222 base (trans) 21 4-py CH₂

1 235-236 hydrochlorid 22 4-py CH₂

2 198-200 hydrochloride 23 4-py CO Ph 2 208-211 hydrochloride 24 4-pyCH₂

2 223-226 hydrochloride 25 4-py CH₂ CF₃ 2 262-264 hydrochloride 26 4-pyCH₂

1 175-177 base 27 4-py CO

1 231 hydrochloride 28 4-py CO

1 264-265 hydrochloride 29 4-py CO

1 231-232 hydrochloride 30 4-py CO

1 272-274 hydrochloride 31 4-py CO

1 266 Hydrochloride 32 4-py CO

1 232 hydrochloride 33 4-py CO

1 268-269 hydrochloride 34 4-py CH(OH) (rac)

1 219-220 base 35 4-py CH(OH) (rac)

1 217-218 hydrochloride 36 4-py CH(OH) (rac)

1 212-213 Hydrochloride

Test Example

[0128] Inhibitory Activity of the Medicament of th Present Inv ntionAgainst GSK3β:

[0129] Two different protocols can be used.

[0130] In a first protocol: 7.5 μM of prephosphorylated GS1 peptide and10 μM ATP (containing 300,000 cpm of 33P-ATP) were incubated in 25 mMTris-HCI, pH 7.5, 0.6 mM DTT, 6 mM MgCl₂, 0.6 mM EGTA, 0.05 mg/ml BSAbuffer for 1 hour at room temperature in the presence of GSK3beta (totalreaction volume: 100 microliters).

[0131] In a second protocol : 4.1 μM of prephosphorylated GS1 peptideand 42 μM ATP (containing 260,000 cpm 33P-ATP) were incubated in 80 mMMes-NaOH, pH 6.5, 1 mM Mg acetate, 0.5 mM EGTA, 5 mM 2-mercaptoethanol,0.02% Tween 20, 10% glycerol buffer for 2 hours at room temperature inthe presence of GSK3beta. Inhibitors were solubilised in DMSO (finalsolvent concentration in. the reaction medium, 1%).

[0132] The reaction was stopped with 100 microliters of a solution madeof 25 g polyphosphoric acid (85% P₂O₅), 126 ml 85% H₃PO₄, H₂O to 500 mland then diluted to 1:100 before use. An aliquot of the reaction mixturewas then transferred to Whatman P81 cation exchange filters and rinsedwith the solution described above. Incorporated 33P radioactivity wasdetermined by liquid scintillation spectrometry.

[0133] The phosphorylated GS-1 peptide had the following sequence:

[0134] NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH.

[0135] The GSK3β inhibitory activity of the compounds of the presentinvention are expressed in IC₅₀, and as an illustration the range ofIC₅₀'s of the compounds in table 1 is between 10 nanomolar to 1micromolar concentrations.

Formulation Example

[0136] (1) Tablets

[0137] The ingredients below were mixed by an ordinary method andcompressed by using a conventional apparatus. Compound of Example 1  30mg Crystalline cellulose  60 mg Corn starch 100 mg Lactose 200 mgMagnesium stearate  4 mg

[0138] (2) Soft Capsules

[0139] The ingredients below were mixed by an ordinary method and filledin soft capsules. Compound of Example 1  30 mg Olive oil 300 mg Lecithin 20 mg

[0140] (1) Parenteral Preparations

[0141] The ingredients below were mixed by an ordinary method to prepareinjections contained in a 1 ml ampoule. Compound of Example 1 3 mgSodium chloride 4 mg Distilled water for injection 1 ml

[0142] Industrial Applicability

[0143] The compounds of the present invention have GSK3β inhibitoryactivity and are useful as an active ingredient of a medicament forpreventive and/or therapeutic treatment of diseases caused by abnormalactivity of GSK3β and more particularly of neurodegenerative diseases.

What is claimed is:
 1. An imidazo[1,2-a]pyrimidone derivativerepresented by formula (I) or a salt thereof, or a solvate thereof or ahydrate thereof:

wherein: X represents a bond, an ethenylene group, an ethynylene group,a methylene group optionally substituted by one or two groups selectedfrom a C₁₋₆ alkyl group, a hydroxy group and a C₁₋₄ alkoxy group; acarbonyl group, an oxygen atom, a sulfur atom, a sulfonyl group, asulfoxide group or a nitrogen atom being optionally substituted by aC₁₋₆ alkyl group; R1 represents a 2, 3 or 4pyridyl group optionallysubstituted by a C₁₋₄ alkyl group, C₁₋₄ alkoxy group or a halogen atom;R2 represents a C₁₋₆ alkyl group, a C₁₋₂ perhalogenated alkyl group, aC₁₋₃ halogenated alkyl group, a benzyl group, a phenyl ring, a naphthylring, 5,6,7,8-tetrahydronaphthyl ring, a pyridyl ring, an indole ring, apyrrole ring, a thiophene ring, a furan ring or an imidazole ring, thebenzyl group and the rings being optionally substituted by 1 to 4substituents selected from a C₁₋₆ alkyl group, a phenyl ring, a halogenatom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃ halogenated alkyl group,a hydroxyl group, a C₁₋₄ alkoxy group, a nitro, a cyano, an amino, aC₁₋₆ monoalkylamino group or a C₂₋₁₀ dialkylamino group; and nrepresents 0 to
 3. 2. An imidazo[1,2-a]pyrimidone derivative or a saltthereof, or a solvate thereof or a hydrate thereof according to claim 1,wherein R1 represents an unsubstituted 4-pyridyl group or 3-pyridylgroup.
 3. An imidazo[1,2-a]pyrimidone derivative or a salt thereof, or asolvate thereof or a hydrate thereof according to claim 1 or 2, atrifluoromethyl group, a 2,2,2-trifluoroethyl, a phenyl ring, a naphthylring, a 5,6,7,8-tetrahydronaphthyl ring or an indole ring, the ringsbeing optionally substituted.
 4. An imidazo[1,2-a]pyrimidone derivativewhich is selected from the group consisting of:1:1-[2-(phenyl)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,2:1-[2-(1H-indol-3-yl)ethyl]-7-pyridinylimidazo[1,2-a]pyrimidin-5(1H)-one,3:1-[3-(phenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,4:1-[3-(1H-indol-3-yl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,5:1-[3-(4-methoxyphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one6:1-[2-(phenoxy)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one7:1-[3-(2-methoxyphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one8:1-[3-(2-chlorophenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one9:1-[3-(2-methylphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one10:1-[2-(phenylthio)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,11:1-[3-(2,5-dimethoxyphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one12:1-[3-(4-methylphenyl)propyl]-7-pyridinylimidazo[1,2-a]pyrimidin-5(1H)-one13:1-[3-(4-trifuoromethylphenyl)propyl]-7-pyridinylimidazo[1,2-a]pyrimidin-5(1H)-one,14:1-[4-(phenyl)butyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,15:1-[3-(phenyl)propyl]-7-pyridin-3-ylimidazo[1,2-a]pyrimidin-5(1H)-one,16:1-(2-phenyl-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,17:(S)1-(4,4,4-trifluoro-3-hydroxybutyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,18:1-(4,4,4-trifluorobut-2-enyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,19:(R)-1-(4,4,4-trifluoro-3-hydroxybutyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,20:1-(4,4,4-trifluorobut-1-enyl)-7-pyridinylimidazo[1,2-a]pyrimidin-5(1H)-one,21:1-[2-(2,5-dimethoxyphenyl)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,22:1-[3-(2-fluorophenyl)propyl]-7-pyridinylimidazo[1,2-a]pyrimidin-5(1H)-one23:1-(3-phenyl-3-oxo-propyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,24:1-[3-(pyridin-3-yl)propyl]-7-pyridinlylimidazo[1,2-a]pyrimidin-5(1H)-one,25:(S)-1-(4,4,4-trifluoro-butyl-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,26:1-[2-(2-methoxyphenyl)ethyl]-7-pyridinylimidazo[1,2-a]pyrimidin-5(1H)-one,27:1-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,28:1-[2-(4-phenyl-phenyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,29:1-[2-(3-methoxyphenyl)-2-oxo-ethyl]-7-pyridinylimidazo[1,2-a]pyrimidin-5(1H)-one,30:1-[2-(2-naphthyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,31:1-[2-(4-mthylphenyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,32:1-[2-(4-fluorophenyl)-2-oxo-ethyl]-7-pyridinylimidazo[1,2-a]pyrimidin-5(1H)-one,33:1-[2-(4-chlorophenyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,34:1-(2-(4-fluorophenyl2-hydroxyethyl)-7-pyridin-4ylimidazo[1,2-a]pyrimidin-5(1H)-one,35:1-(2-naphthyl-2-hydroxyethyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,36:1-(2-(1,1,4,4,-tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-2-hydroxyethyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,or a salt thereof, or a solvate thereof or a hydrate thereof.
 5. Amedicament comprising as an active ingredient a substance selected fromthe group consisting of an imidazo[1,2-a]pyrimidone derivativerepresented by formula (I) or salts thereof, or a solvate thereof or ahydrate thereof according to claim
 1. 6. A GSK3β inhibitor selected fromthe group of a imidazo[1,2-a]pyrimidone derivative represented byformula (I) or salts thereof, or a solvate thereof or a hydrate thereofaccording to claim
 1. 7. Use of a compound according to claims 1 to 4for the preparation of a medicament for preventive and/or therapeutictreatment of a disease caused by abnormal GSK3β activity.
 8. Use of acompound according to claims 1 to 4 for the preparation of a medicamentfor preventive and/or therapeutic treatment of a neurodegenerativedisease.
 9. Use of a compound according to claim 8, wherein theneurodegenerative disease is selected from the group consisting ofAlzheimer's disease, Parkinson's disease, tauopathies, vasculardementia; acute stroke, traumatic injuries; cerebrovascular accidents,brain cord trauma, spinal cord trauma; peripheral neuropathies;retinopathies or glaucoma.
 10. Use of a compound according to claims 1to 4 for the preparation of a medicament for preventive and/ortherapeutic treatment of non-insulin dependent diabetes; obesity; manicdepressive illness; schizophrenia; alopecia; or cancers.
 11. Useaccording to claim 10 wherein cancer is breast cancer, non-small celllung carcinoma, thyroid cancer, T or B-cell leukemia or virus-inducedtumors.